An Intravenous Study with the Radiolabeled sGC Stimulator Frespaciguat to Assess PK, Metabolism, and Mass Balance

Abstract Pulmonary hypertension (PH) is a chronic disorder characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. PH can develop in patients with chronic obstructive pulmonary disease (COPD), resulting in greater morbidity and mortality than either condition alone. Current treatment options for PH‐COPD are limited, and systemic vasodilators often cause adverse effects. Frespaciguat (MK‐5475), an inhaled soluble guanylate cyclase stimulator, is being studied for its potential to selectively reduce pulmonary vascular pressures with minimal systemic exposure. This study aimed to characterize the pharmacokinetics (PK), metabolism, elimination, safety, and tolerability of frespaciguat in healthy male participants following a single 100 µg intravenous dose of [ 14 C]frespaciguat using a low radioactive dose. The PK of frespaciguat is characterized by moderate clearance and a short half‐life of approximately 2 h. The drug is predominantly eliminated via the biliary–fecal route, with metabolism playing a major role. Frespaciguat and its metabolites were well tolerated, with no severe adverse events reported. The study demonstrated that frespaciguat is extensively metabolized, likely via enzymes involved in β‐oxidation, and is primarily excreted in feces. The human mass balance and metabolism study suggests that frespaciguat's metabolism may be impacted by inhibitors of β‐oxidation enzymes. These findings support the potential of frespaciguat as a targeted treatment for PH‐COPD, offering a promising therapeutic approach with minimal systemic side effects.